The ability to distinguish self from non-self is essential in maintaining proper immune homeostasis. Most self-reactive T cells are eliminated in the thymus through negative selection; however some cells bearing T cell receptors that recognize self-proteins may still escape thymic selection and enter the peripheral system as mature T cells. To avoid autoimmunity, those cells must be inactivated. Anergy is of one of the mechanisms that ensure proper control of self-reactive T cells. CD4+ T cells become anergic or unresponsive to antigen following suboptimal or partial stimulation. In T helper cells, anergy is established as a consequence of the NFAT-dependent expression of a specific set of anergy-associated genes, which encode proteins that dampen TCR signaling and inhibit cytokine transcription. Several reports have also identified T cell anergy as an important mechanism of immune evasion induced by malignant tumors. Although evidence suggests that T cell anergy may play a key role in preventing autoimmune disease and facilitating the ability of cancer cells to evade immune responses, the precise role that T cell anergy plays in regulating T cell responses in vivo remains yet to be fully addressed. With this proposal we intend to further characterize the transcriptional mechanisms that regulate the induction of T cell anergy and use that knowledge to evaluate the specific role of T cell anergy in two different processes: maintenance of self tolerance and tumor-induced immune tolerance; and finally 3. Develop a strategy to regulate the induction of T cell anergy and evaluate its possible use a therapeutic tool. A detailed understanding of the regulation and the physiological role of T cell anergy and the identification of new targets to specifically modulate this process should provide valuable information to design strategies for the treatment of autoimmune diseases, to prevent graft rejection or to activate T cell responses against tumor cells or during chronic infections. PUBLIC HEALTH RELEVANCE: Inactivation of self-reactive T cells has been identified as an important mechanism in the control of immune reactions against our own tissues. This process, termed anergy, is also crucial to understand how chronic infections and cancer cells can evade effective immune responses. The aim of this project is to characterize the molecular mechanisms that control how T cells anergy is established and, based on that knowledge, develop potential therapeutic strategies that may help enhance T cell responses against cancer cells and chronic pathogens.